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CAS No. : | 314771-76-1 | MDL No. : | MFCD18642925 |
Formula : | C18H16ClFN4O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BIQABKFYKJRXII-NSHDSACASA-N |
M.W : | 374.80 | Pubchem ID : | 15606392 |
Synonyms : |
|
Num. heavy atoms : | 26 |
Num. arom. heavy atoms : | 16 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 98.34 |
TPSA : | 82.29 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.12 cm/s |
Log Po/w (iLOGP) : | 2.9 |
Log Po/w (XLOGP3) : | 3.48 |
Log Po/w (WLOGP) : | 4.34 |
Log Po/w (MLOGP) : | 2.74 |
Log Po/w (SILICOS-IT) : | 3.26 |
Consensus Log Po/w : | 3.34 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.55 |
Solubility : | 0.0106 mg/ml ; 0.0000283 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.89 |
Solubility : | 0.00482 mg/ml ; 0.0000129 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.74 |
Solubility : | 0.000069 mg/ml ; 0.000000184 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.29 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | (E)-4-Dimethylaminocroton hydrochloride 9.65 g was sequentially added to a 500 ml four-necked flask.93 g of N-methylpyrrolidone was stirred and cooled to -5 C, and 6.6 g of thionyl chloride was slowly added dropwise to the stirring solution to ensure that the temperature of the reaction solution was between 0 and -5 C, and within the above temperature range after the completion of the dropwise addition. Take a fall of 20min.N-4-[(3-chloro-4-fluorophenyl)]-7-[(3S)-tetrahydrofuran-3-yl]oxy}-4,6-quinazolinediamine 12.45g Dissolved in 62g of N-methylpyrrolidone as a dropping solution,Slowly add this solution to the above stirring solution and ensure that the temperature is between 0 and -5 C.After the completion of the dropwise addition, the mixture was stirred for 15 minutes in the above temperature range to obtain an acylation reaction liquid.Then, 100 g of water is slowly added dropwise to the above reaction solution and the temperature is controlled to not exceed 15 C, and then a 20% NaHH solution is slowly added dropwise thereto to about 66.3 g to rho Eta = 9 to 10, and the controlled temperature does not exceed 25 during the dropwise addition. C. After the dropwise addition, the reaction liquid was extracted three times (353 g X 3 ) with butyl acetate at 45 C, and the organic phase was collected, washed with water at 45 C for 5 times (250 g X 5 ), and then directly stirred for crystallization (stirring and crystallization) The temperature is selected from the table shown in Table 2) 3h. Filtration, crystals, butyl acetate 53g rinse the filter cake once, and finally dried under vacuum at 40 C for 2h to obtain a white solid. The yield, yield, purity and content of impurity I are shown in Table 2. | |
93% | With Bromoform; triethylamine; triphenylphosphine; In dichloromethane; at 25℃; for 1h; | 50.1 g of dimethylamino croton hydrochloride,108.0 g of N4-(3-chloro-4-fluoro-phenyl)-7-((S)-tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine,84.2 mL of triethylamine and 100.3 g of carbon tetrabromide were dissolved in dry 1944 mL of dichloromethane, and 79.4 g of triphenylphosphine was added in portions at 25 C with stirring.After 60 min, the reaction was filtered, and the filtrate was washed with water (1900 mL×2×).The residue was recrystallized from 390 mL of isopropanol to give 130.2 g of afatinib.The molar yield was 93% and the product purity was 98%. |
87.4% | (1) To the 1 L bottle is added in three trans -4 - dimethylamino crotonic acid hydrochloride 50 g, N - methyl pyrrolidone 100 g, ethyl acetate 400 g, cooled to 5 C, to the system adds by drops the chlorination sulfoxide 36.1 g, after dropping, 5 C conditions under stirring, HPLC monitoring to the reaction is complete (SM1 residue 1.8%). (2) Will be N4 - (3 - chloro -4 - fluoro - phenyl) -7 - (S)- tetrahydrofuran -3 - oxyacetyl) quinazoline - 4, 6, - diamine (SM2) 45 g N - methyl pyrrolidone for 225 g dissolved, the solution is dropped is added to step (1) in the reaction system, after dropping, 0 C reaction, TLC monitoring reaction to SM2 reaction is complete. (3) Temperature control 20 C following, to the step (2) in the system drop of pure water 1.35 kg, for 20 weight % sodium hydroxide solution to adjust pH=9, ethyl acetate 675 g * 2 extraction, control gathering temperature is 45 C, combined with the organic phase, purified water 0.9 kg * 2 washing, organic phase in the 45 C concentrated under reduced pressure to V (the remaining system)/m (SM2) is about 10, lowering the temperature to -5 C, crystallization 2 hr, filtered, the filter cake in the 50 C vacuum drying, to obtain yellowish solid 51 g, yield 87.4%. The detection HPLC purity of 99.6%. |
48 g | A mixture of (E)-4-(dimethylamino) but-2-enoic acid hydrochloride (44.1 g) and dimethyl acetamide (350 ml) was cooled at -15 to -20 C. To this solution 28.6 g of thionyl chloride was added dropwise and stirred at -15 to -20 C for 3-4 h (designated as solution-i). In a separate container N4-(3-chloro-4-fluorophenyl)-7- [(3 S)-tetrahydrofuran-3 -yloxy] quinazoline-4, 6-di amine (50 g) was dissolved in150 ml dimethylacetamide and added to the solution-i at -20 to -25 C. The reaction mixture was stirred for 1-2 h. To this reaction mass charged water (100 ml) followed by stirring for 10 min(designated as solution-2). A solution of sodium carbonate prepared separately by dissolving 125g potassium carbonate in 1900 ml of purified water(designated as solution-3). The solution-2 was addedinto the solution-3 and solid obtained stirred for 2-3hr. The solid was filtered and suspended in water and pH adjusted to 2-5 using hydrochloric acid solution. Ethyl acetate (500m1) added and reaction mass stirred for i-i.5h. Ethyl acetate layer separated and discarded. The aqueous layer was neutralized with potassium carbonate and pH was maintained at around 8-9. The solid obtained stirred forfurther 2h and filtered followed by drying to get 48g of the Afatinib. | |
(E)-4-(dimethylaminobut-2-enoic acid) hydrochloride (44.1 g)And dimethylacetamide (350mL)The mixture is cooled at -10 to -20 C.To the solution, 28.6 g of thionyl chloride was added dropwise and stirred at -10 to -20 C for 3-4 h (designated as solution-1).In another container,(S)-N4-(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine (50g dissolved in 150mL dimethylacetamide, -20--25Add to solution-1 below,Stir the reaction for 1-2h,Add 100 mL to the reaction solution.Stir for 10 min (referred to as solution-2).A sodium carbonate solution (referred to as solution-3) was prepared by dissolving 125 g of potassium carbonate in 1900 mL of purified water.Add Solution-2 to Solution-3,Stir the solid for 2-3 h, filter,The solid was suspended in water and the pH was adjusted to 2-5 with a hydrochloric acid solution.Ethyl acetate (500 mL) was mixed with the solution and stirred for 1 h.The ethyl acetate layer was separated and discarded.The aqueous layer was neutralized with potassium carbonate and the pH was maintained at around 8-9.The resulting solid was stirred for additional 2 h and filtered.It was then dried to give 48 g of afatinib free base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 30 - 55 °C 1.2: 3 h / 20 - 40 °C 2.1: lithium chloride; potassium hydroxide / ethanol; water / 2 h / -5 - 10 °C / Inert atmosphere 2.2: 7 h / 0 - 18 °C 3.1: ethanol / 10 - 15 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | Stage #1: diphenylphosphorylacetic acid With phosphorus trichloride In dichloromethane at 0 - 20℃; for 1.5h; Stage #2: 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline With triethylamine In dichloromethane at 20℃; for 1.5h; | 1; 5 Example 5 Preparation of afatinib maleate Phosphorus trichloride (4.94g, 0.036mol) Slowly dripping diphenylphosphine acetic acid(23.42g, 0.09mol) is soluble 250mL anhydrous dichloromethane solution,The reaction temperature was controlled to 0 °C. The mixture was stirred at 20 ° C for 1.5 hours and then cooled to 0 ° C. Triethylamine (10.12g, 0.1mol) and 4-[(3-Chloro-4-fluorophenyl)-amino]-6-amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline (33.73 g, 0.09 mol) Soluble in 250mL anhydrous dichloromethane solution slowly into the above solution,After the completion of the dropwise addition, the reaction was carried out at 20 ° C for 1.5 hours. After the TLC monitoring reaction was completed, 200 mL of purified water was added to the extract layer.The organic phase was washed with 200 mL of purified water.Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to oil.Add tetrahydrofuran / isopropyl ether (1:1) 400mL recrystallization to give a white solid 52.75g,Yield: 94.9%. |
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